Kim Se-Jin, Peterson Jessie C, Olive Andrew J, Tafesse Fikadu G, Kulicke Corinna A, Karamooz Elham, Lewinsohn David M
Division of Pulmonary, Allergy, and Critical Care Medicine, Oregon Health & Science University, Portland, OR 97239, USA.
Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR 97239, USA.
bioRxiv. 2025 Jun 26:2025.06.23.660389. doi: 10.1101/2025.06.23.660389.
(Mtb) is an intracellular pathogen that can be sensed by T cells, which are essential for the control of infection. In comparison to viral infections, Mtb antigens are relatively rare and hence, challenging to sample. Specialized antigen presentation pathways enable the presentation of such scarce antigens to CD8 T cells, which are, thus, uniquely poised to survey intracellular environments. A subset of CD8 T cells prevalent in the airways, known as mucosal associated invariant T (MAIT) cells, can be activated through the presentation of Mtb antigens via the MHC class I-related protein 1 (MR1) molecule. Prior work demonstrates that endosomal calcium signaling is critical for MR1-mediated presentation of Mtb-derived antigens. Here, we show that the calcium-sensing trafficking proteins Synaptotagmin (Syt) 1 and Syt7 specifically promote MAIT cell activation in response to Mtb-infected cells. In bronchial epithelial cells, Syt1 and Syt7 localize to late endo-lysosomes and MR1 vesicles. Loss of Syt1 and Syt7 results in enlarged MR1 vesicles and an increased number of MR1 vesicles in close proximity to Mtb-containing vacuoles during infection. This study identifies a novel pathway in which Syt1 and Syt7 facilitate the translocation of MR1 from Mtb-containing vacuoles, potentially to the cell surface for antigen presentation.
结核分枝杆菌（Mtb）是一种细胞内病原体，可被T细胞识别，而T细胞对于控制感染至关重要。与病毒感染相比，Mtb抗原相对稀少，因此采样具有挑战性。专门的抗原呈递途径能够将此类稀缺抗原呈递给CD8 T细胞，因此，CD8 T细胞特别适合监测细胞内环境。气道中普遍存在的一部分CD8 T细胞，称为黏膜相关恒定T（MAIT）细胞，可通过MHC I类相关蛋白1（MR1）分子呈递Mtb抗原而被激活。先前的研究表明，内体钙信号传导对于MR1介导的Mtb衍生抗原呈递至关重要。在这里，我们表明钙感知转运蛋白突触结合蛋白（Syt）1和Syt7特异性促进MAIT细胞对Mtb感染细胞的反应激活。在支气管上皮细胞中，Syt1和Syt7定位于晚期内溶酶体和MR1囊泡。Syt1和Syt7的缺失导致MR1囊泡增大，并且在感染期间靠近含Mtb液泡的MR1囊泡数量增加。这项研究确定了一条新途径，其中Syt1和Syt7促进MR1从含Mtb液泡的转运，可能转运到细胞表面进行抗原呈递。
